The mechanism by which fibrinogen heterogeneity is induced will be studied in vitro, in animal models and certain groups of patients. The concept of an intermediate solid phase in this process in which the high molecular weight (HMW) fraction is first precipitated remains our leading hypothesis. These studies will utilize a previously developed electrophoretic technique which permits direct measurement of various fibrinogen fractions and is sensitive to greater than or equal to 4 mg% of protein. Since the HMW fraction has a shorter clotting time, it is postulated that it may represent the predominant substrate for fibrin monomer (FM) formation. The role of a solid phase in the catabolism of soluble FM will also be investigated with particular emphasis on the role of leukocytes and platelets in the precipitation of FM, and on the mechanism by which a high fibrinogen concentration appears to potentiate FM precipitation. These studies will utilize animal models in which fibrin deposition in various organs can be measured quantitatively and in which thrombosis in areas of venous stasis is evaluated. The pathogenesis of disseminated intravascular coagulation (DIC) will be investigated in these models with particular emphasis on the role of insoluble (particle bound) versus soluble procoagulant triggers of intravascular fibrin formation. The identity of a tissue fraction which triggers DIC but has no thromboplastic activity will continue to be explored as will the role of leukocytes in endotoxin induced DIC. The role of tissue versus blood fibrinolytic activity in the clearance of fibrin deposits will also be invested in these animal models. It is postulated that tissue fibrinolytic activity (activator content) is of predominant importance in DIC but not in major vessel thrombosis. New methods and concepts arising from the laboratory will be applied to studies of patients with DIC and occlusive vascular disease.